Dr. Susan Thomas (Georgia Institute of Technology)
Dr. Andrés García (Georgia Institute of Technology)
Dr. Krishnendu Roy (Georgia Institute of Technology)
Dr. Shuichi Takayama (Georgia Institute of Technology)
Dr. Edmund Waller (Emory University)
Adhesion analysis of CD8+ T cells using engineered microfluidic platforms to interrogate extravasation capacity for adoptive cell therapy
Adoptive cell therapy (ACT) has emerged as a powerful treatment option for patients with metastatic melanoma. Despite encouraging results with this treatment modality, responses are seen in only a minority of patients. It is now known that low patient rates of response are due to poor tumor-infiltrating lymphocytes (TIL) survival post transfer as well as poor trafficking of transferred cells to relevant tissues. In order for TILs to infiltrate disease tissue from the blood vasculature, they utilize a highly orchestrated adhesion cascade that begins with selectin-mediated rolling adhesion to endothelial cells, followed by integrin mediated firm adhesion and subsequent extravasation. These adhesion ligand-receptor interactions have been implicated in TIL homing, however, an outstanding problem in the field is a lack of understanding how TIL’s surface adhesion ligands initiate and sustain adhesion interactions with the tumor vasculature, and how this may lead to improved engraftment of TILs to the tumor microenvironment. As such, the overall objective of this project is to utilize engineered microfluidic devices that enable the interrogation of adhesive behavior of cells under relevant hemodynamic forces to 1) analyze how cell adhesion is regulated by different microenvironments of the tumor vasculature and 2) determine what adhesion receptors, cytokines, and activation markers are present in highly adhesive cells. My central hypothesis is that microfluidic devices can be implemented to mimic the hemodynamic environment of the tumor vasculature to interrogate cellular characteristics such as adhesion ligand expression, activation and differentiation state of TILs associated with adhesion in flow. This work will provide insight into which TIL’s subpopulation is the most appropriate for enhanced tumor homing for ACT.